Platinum complex

ABSTRACT

A platinum complex having a superior antitumor activity is disclosed. The platinum complex has a structure represented by the formula: ##STR1## wherein A and B independently represent a lower alkanoyloxy group which may have a halogen atom substituent, or in combination represent a group: ##STR2## wherein R 1  and R 2  independently represent a hydrogen atom, a hydroxyl group, or a lower alkyl group, or in combination with each other and with the adjacent carbon atom a cyclobutane ring, and R 3  represents a hydrogen atom, a lower alkyl group, a lower alkoxy group, a halogen atom, a sulfo group, or nitro group.

BACKGROUND OF THE INVENTION

1. Field of the Invention

This invention relates to a platinum complex having a superior antitumoractivity.

2. Description of the Background

Cisplatin, which is a platinum complex reported by Rosenberg et al. as anovel antitumor agent in 1969 [Nature, 222, 385 (1969)] has a wideantitumor spectrum and is used especially as a antitumor agentexhibiting a remarkable effect particularly on genitalia cancer, bladdercancer, and head and neck cancer, or the like. There are a number ofstudies on platinum complexes other than cisplatin. They are reportedfor instance in Japanese Patent Laid-open No. 31648/1978, JapanesePatent Laid-open No. 77694/1982, and the like.

The aforementioned cisplatin is commercially sold as a antitumor agent.The compound, however, has a high toxicity to kidney and other organs,and thus a limitation is imposed to its use. The purpose of theinvention is to provide a platinum complex with a superior antitumoractivity and yet exhibits a lower degree of toxicity.

The inventors have synthesized various platinum complexes having1,3-diamino-2-propanol as a ligand and studied their pharmaceuticaleffects. As a result, the inventors have found that a platinum complexrepresented by the following formula (I) has advantages of a superiorantitumor activity, a low toxicity, and high solubility in water. Thefinding has led to the completion of this invention.

SUMMARY OF THE INVENTION

Accordingly, an object of this invention is to provide a platinumcomplex represented by the following formula (I): ##STR3## wherein A andB independently represent a lower alkanoyloxy group which may have ahalogen atom substituent, or in combination represent a group: ##STR4##wherein R₁ and R₂ independently represent a hydrogen atom, a hydroxylgroup, or a lower alkyl group, or in combination with each other andwith the adjacent carbon atom a cyclobutane ring, and R₃ represents ahydrogen atom, a lower alkyl group, a lower alkoxy group, a halogenatom, a sulfo group, or nitro group.

Other objects, features and advantages of the invention will hereinafterbecome more readily apparent from the following description.

DETAILED DESCRIPTION OF THE INVENTION AND PREFERRED EMBODIMENTS

In formula (I), a lower alkanoyloxy group may be, for example, analkanoyloxy group having 2 to 5 carbon atoms, and a lower alkyl andlower alkoxy groups may be those having 1 to 5 carbon atoms.

The platinum complex of this invention can be prepared, for example,according to the following reaction scheme. ##STR5##

Specifically, according to the above reaction formulae, potassium iodideis added into an aqueous solution of potassium tetrachloroplatinate toproduce an aqueous solution of potassium tetraiodoplatinate. To thissolution 1,3-diamino-2-propanol is added and reacted to give thecompound (II). This compound (II) in an aqueous solution is then treatedwith silver nitrate to prepare a dinitrato complex (III), or with silversulfate to prepare sulfato complex (IV). The target compound (I) of thisinvention is prepared by reacting the dinitrato complex (III) or sulfatocomplex (IV) with a carboxylate.

Given as examples of carboxylates used in the above reaction are saltsof monocarboxylic acid such as acetic acid, propionic acid, butylicacid, chloroacetic acid, bromoacetic acid, or the like; dicarboxylicacid such as oxalic acid, malonic acid, hydoxymalonic acid,methylmalonic acid, dimethylmalonic acid, diethylmalonic acid,1,1-cyclobutanedicarboxylic acid, or the like; glycolic acid, salicylicacid, 3-methylsalicylic acid, 4-methylsalicylic acid, 3-methoxysalicylicacid, 4-methoxysalicylic acid, 5-methoxysalicylic acid, 5-nitrosalicylicacid, 3-chlorosalicylic acid, 4-chlorosalicylic acid, 5-chlorosalicylicacid, 3-sulfosalicylic acid, 5-sulfosalicylic acid, and the like.

Other features of the invention will become apparent in the course ofthe following description of the exemplary embodiments which are givenfor illustration of the invention and are not intended to be limitingthereof.

EXAMPLES Example 1 Preparation of(1,3-diamino-2-propanol)oxalatoplatinum (II) (Compound No. 1)

Into 80 ml of water 4.15 g of potassium tetrachloroplatinate wasdissolved. To the solution was added 16.6 g of potassium iodide and themixture was stirred for 1 hour at room temperature to produce an aqueoussolution of potassium tetraiodoplatinate. To this solution 5 ml of 900mg 1,3-diamino-2-propanol aqueous solution was added dropwise, and themixture was stirred at 60° C. for 5 minutes. The deposited crystals werecollected by filtration and the filtrate was washed with water, acetone,and then ether, and dried in vacuo to obtain 4.72 g of yellow crystalsof (1,3-diamino-2-propanol)cis-diiodoplatinum (II) at a yield of 88%.

1.07 g of cis-diido(1,3-diamino-2-propanol)platinum (II) thus preparedwas suspended into 30 ml of water and to the suspension was added 0.68 gof silver nitrate dissolved into 10 ml of water. The mixture was stirredat room temperature for 3 hours. The produced silver iodide was removedby filtration. To the filtrate 0.368 g of potassium oxalate monohydratewas added and the mixture was stirred at 60° C. for 3 hours. After thereaction, the reaction mixture was cooled at 0° C. The depositedcrystals were collected by filtration, washed with a small amount ofwater, methanol, then ether, and dried in vacuo to obtain 604 mg ofCompound No. 1 in a form of colorless crystals at a yield of 81%.

Example 2 Synthesis of (1,3-diamino-2-propanol)malonatoplatinum (II)(Compound No. 2)

Into 40 ml of water 1.07 g of (1,3-diamino-2-propanol)cis-diiodoplatinum (II) prepared in Example 1 was suspended. To thesuspension waes added 0.62 g of silver sulfate dissolved into 10 ml ofwater. The mixture was stirred at room temperature for 3 hours. Theproduced silver iodide was removed by filtration. The filtrate wascondensed to 15 ml volume and to this was added 0.21 g of malonic acidin 4 ml of 1N sodium hydroxide solution. The mixture was left at roomtemperature for 3 days and the reaction mixture was cooled at 0° C. Thedeposited crystals were collected by filtration, washed with a smallamount of water, ethanol, then ether, and dried in vacuo to obtain 0.59g of Compound No. 2 in a form of colorless crystal at a yield of 75%.

Example 3

Synthesis of (1,1-cyclobutanedicarboxylato)(1,3-diamino-2-propanol)platinum (II) (Compound No. 3)

Into 60 ml of water 1.62 g of (1,3-diamino-2-propanol)cis-diiodoplatinum (II) prepared in Example 1 was suspended. To thesuspension was added 1.02 g of silver nitrate dissolved into 10 ml ofwater. The mixture was stirred at room temperature for 3 hours. Theproduced silver iodide was removed by filtration. To the filtrate wasadded 0.43 g of 1,1-cyclobutanedicarboxylic acid in 6 ml of 1N sodiumhydroxide solution. The mixture was reacted at room temperature for 1day. After the reaction, reaction mixture was condensed and thecondensate was cooled at 0° C. The deposited crystals were collected byfiltration, washed with a small amount of cold water, acetone, thenether, and dried in vacuo to obtain 0.98 g of Compound No. 3 in a formof colorless crystal at a yield of 76%.

Examples 4-7

Compounds No. 4-7 were prepared in the same manner as in Example 3.

Compound No. 4:

(1,3-diamino-2-propanol)hydroxymalonatoplatinum (I)

Compound No. 5:

(1,3-diamino-2-propanol)methylmalonatoplatinum (II)

Compound No. 6:

(1,3-diamino-2-propanol)dimethylmalonatoplatinum (II)

Compound No. 7:

(1,3-diamino-2-propanol)diethylmalonatoplatinum (II)

Example 8 Synthesis of (1,3-diamino-2-propanol)(glycolato-O,O')-platinum(II) (Compound No. 8)

The same procedure as in Example 3 was carried out, except that 0.23 gof glycolic acid was used instead of 1,1-cyclobutanedicarboxylic acid toproduce 0.81 g of Compound No. 8 as colorless crystals at a yield of75%.

Example 9 Synthesis of(1,3-diamino-2-propanol)(salicylato-O,O')-platinum (II) (Compound No. 9)

The same procedure as in Example 1 was carried out, except that 0.48 gof sodium salicylate was used instead of potassium oxalate monohydrateto produce 0.92 g of Compound No. 9 as colorless crystals at a yield of73%.

Examples 10-11

Compound Nos. 10 and 11 were prepared in the same manner as in Example9.

Compound No. 10:

(1,3-diamino-2-propanol)(5-methoxysalicylato-O,O') platinum (II)

Compound No. 11:

(1,3-diamino-2-propanol)(5-sulfosalicylato-O,O') platinum (II)

Example 12 Synthesis of bis(chloroacetato)(1,3-diamino-2-propanol)platinum (II) (Compound No. 12)

The same procedure as in Example 3 was carried out, except that 0.57 gof chloroacetic acid was used instead of 1,1-cyclobutanedicarboxylicacid to produce 0.99 g of Compound No. 12 as colorless crystals at ayield of 70%.

Physicochemical characteristics of Compound Nos. 1 to 12 thus preparedare shown in Table 1.

                                      TABLE 1                                     __________________________________________________________________________     ##STR6##                                                    (I)              Com-                        FAB-MS         Elemental Analysis                 pound                                                                             In Formula (I)          (.sup.195 Pt)  Calculated (Found)                                                                      Characteristics          No. A, B           IR ν.sub.max.sup.KBr cm.sup.-1                                                      (M + H).sup.+  C   H  N  Melting Point                                                                 (°C.)             __________________________________________________________________________         ##STR7##      3400, 3250, 3150 1700, 1670, 1390                                                      374   C.sub.5 H.sub.10 N.sub.2 O.sub.5                                                       16.09 (15.91                                                                      2.70 2.64                                                                        7.51 7.48)                                                                       Colorless crystals                                                            185-197 (decomp.)        2                                                                                  ##STR8##       3300, 3230, 3130 1670, 1640, 1620 1590,                                               3885  C.sub.6 H.sub.12 N.sub.2 O.sub.5                                                       18.61 (18.45                                                                      3.12 2.99                                                                        7.23 7.06)                                                                       Colorless crystals                                                            223-233 (decomp.)        3                                                                                  ##STR9##      3450, 3250, 3150 1630, 1380                                                            428   C.sub.9 H.sub.16 N.sub.2 O.sub.5                                                       25.30 (25.08                                                                      3.77 3.97                                                                        6.56 6.40)                                                                       Colorless crystals                                                            225-233 (decomp.)        4                                                                                  ##STR10##     3500, 3400, 3220 3150, 1640-1680                                                       404   C.sub.6 H.sub.12 N.sub.2 O.sub.6                                                       17.87 (17.71                                                                      3.00 2.84                                                                        6.95 7.19)                                                                       Colorless crystals                                                            215-230 (decomp.)        5                                                                                  ##STR11##     3450, 3220, 3120 1670, 1630, 1400 1390                                                 402   C.sub.7 H.sub.14 N.sub.2 O.sub.5                                                       20.95 (20.85                                                                      3.52 3.67                                                                        6.98 6.73)                                                                       Colorless crystals                                                            195-210 (decomp.)        6                                                                                  ##STR12##     3400, 3250, 3150 1620, 1600                                                            416   C.sub.8 H.sub.16 N.sub.2 O.sub.5                                                       23.14 (23.07                                                                      3.88 3.89                                                                        6.75 6.65)                                                                       Colorless crystals                                                            205-215 (decomp.)        7                                                                                  ##STR13##     3600, 3450, 3210 1615, 1560                                                            444   C.sub.10 H.sub.20 N.sub.2 O.sub.5                                                      27.09 (27.01                                                                      4.55 4.59                                                                        6.32 6.23)                                                                       Colorless crystals                                                            215-230 (decomp.)        8                                                                                  ##STR14##     3530, 3350, 3200  3100, 1620, 1590 1370                                                360   C.sub.5 H.sub.12 N.sub.2 O.sub.4                                                       16.72 (16.81                                                                      3.37 3.43                                                                        7.80 7.67)                                                                       Colorless crystals                                                            180-189 (decomp.)        9                                                                                  ##STR15##     3450, 3250, 3150 1610, 1590                                                            422   C.sub.10 H.sub.14 N.sub.2 O.sub.4                                                      28.51 (28.44                                                                      3.35 3.41                                                                        6.65 6.58)                                                                       Colorless crystals                                                            240-255 (decomp.)        10                                                                                 ##STR16##     3450, 3250, 3150 1645, 1620                                                            452   C.sub.11 H.sub.16 N.sub.2 O.sub.5                                                      29.27 (29.37                                                                      3.57 3.66                                                                        6.21 6.07)                                                                       Colorless crystals                                                            145-155 (decomp.)        11                                                                                 ##STR17##     3450, 3250, 3150 1605                                                                  502   C.sub.10 H.sub.14 N.sub.2 O.sub.7                                                      23.96 (24.08                                                                      2.81 2.88                                                                        5.59 5.49)                                                                       Colorless crystals                                                            220-235 (decomp.)        12                                                                                 ##STR18##     3400, 3250, 3150 1630                                                                  472   C.sub.7 H.sub.14 N.sub.2 O.sub.5                                              Cl.sub.2 Pt                                                                            17.81 (17.89                                                                      2.99 3.07                                                                        5.93 5.82)                                                                       Colorless crystals                                                            115-130                  __________________________________________________________________________                                                         (decomp.)            

EXPERIMENT EXAMPLES

Antitumor activity of the compound of this invention is now illustratedby an experimental example.

(Test Method)

CDF₁ male mice (age: 6 weeks) consisting of 6 per each group wereprovided to the test. 1×10⁶ mouse L-1210 leukemia cells wereintraperitoneally inoculated into each mouse. Starting from the firstday of inoculation, each test compound dissolved into 0.5% CMC-Nacontaining 0.8% of sodium chloride was intraperitoneally administered toeach mouse once a day for 5 consecutive days. Physiological saline wasadministered to the group of mice untreated by a test compound.Cisplatin and carboplatin, both are known compounds, were administeredto the mice of the control groups.

Increase life span (ILS) was determined according to the followingequation.

    ILS=(T/C-1)×100(%)

wherein T is average days of survival of the treated groups, and C isthe corresponding average days of survival of the control groups.

The results are shown in Table 2.

                  TABLE 2                                                         ______________________________________                                                                         Number of mice                                                                survived for 30                              Compound   Dose (mg/kg)                                                                             ILS (%)    days or more                                 ______________________________________                                        Compound No. 2                                                                           32 × 5                                                                             >129       5                                            Compound No. 3                                                                           8 × 5                                                                              >143       6                                            Cisplatin  2 × 5                                                                              >113       1                                            Carboplatin                                                                              16 × 5                                                                             >109       3                                            ______________________________________                                    

The compound of this invention has a superior antitumor effect, exhibitsa low toxicity, and is abundantly soluble in water, and thus is usefulas antitumor agent.

Obviously, numerous modifications and variations of the presentinvention are possible in light of the above teachings. It is thereforeto be understood that the scope of the appended claims, the inventionmay be practiced otherwise than as specifically described herein.

What is claimed as new and desired to be secured by Letters Patentis:
 1. The compound which isbis(chloroacetato)(1,3-diamino-2-propanol)platinum (II).